Microtubule disruption synergizes with oncolytic virotherapy by inhibiting interferon translation and potentiating bystander killing.

Rozanne Arulanandam, Cory Batenchuk, Oliver Varette, Chadi Zakaria, Vanessa Garcia, Nicole E Forbes, Colin Davis, Ramya Krishnan, Raunak Karmacharya, Julie Cox, Anisha Sinha, Andrew Babawy, Katherine Waite, Erica Weinstein, Theresa Falls, Andrew Chen, Jeff Hamill, Naomi De Silva, David P Conrad, Harold Atkins, Kenneth Garson, Carolina Ilkow, Mads Kærn, Barbara Vanderhyden, Nahum Sonenberg, Tommy Alain, Fabrice Le Boeuf, John C Bell, Jean-Simon Diallo

Index: Nat. Commun. 6 , 6410, (2015)

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Abstract

In this study, we show that several microtubule-destabilizing agents used for decades for treatment of cancer and other diseases also sensitize cancer cells to oncolytic rhabdoviruses and improve therapeutic outcomes in resistant murine cancer models. Drug-induced microtubule destabilization leads to superior viral spread in cancer cells by disrupting type I IFN mRNA translation, leading to decreased IFN protein expression and secretion. Furthermore, microtubule-destabilizing agents specifically promote cancer cell death following stimulation by a subset of infection-induced cytokines, thereby increasing viral bystander effects. This study reveals a previously unappreciated role for microtubule structures in the regulation of the innate cellular antiviral response and demonstrates that unexpected combinations of approved chemotherapeutics and biological agents can lead to improved therapeutic outcomes.